|Publication number||US7612563 B2|
|Application number||US 11/905,637|
|Publication date||Nov 3, 2009|
|Filing date||Oct 3, 2007|
|Priority date||Oct 26, 2006|
|Also published as||EP1918730A1, EP1918730B1, US20080100296|
|Publication number||11905637, 905637, US 7612563 B2, US 7612563B2, US-B2-7612563, US7612563 B2, US7612563B2|
|Inventors||Charles Massin, Michael Fey|
|Original Assignee||Bruker Biospin Ag|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (17), Non-Patent Citations (8), Referenced by (6), Classifications (6), Legal Events (3)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application claims Paris Convention priority of EP 06 022 373.2 filed Oct. 26, 2006 the complete disclosure of which is hereby incorporated by reference.
The invention concerns a flow-through microfluidic nuclear magnetic resonance (=NMR)-chip comprising a substrate which is planar in an yz-plane with a sample chamber within the substrate, the sample chamber being elongated and having walls which run parallel to the z-direction the substrate having a thickness in x-direction of a Cartesian xyz-coordinate system between 50 μm and 2 mm, and at least one planar receiving and/or transmission coil with conductor sections the coil being arranged at least on one planar surface of the substrate, wherein the extension of the sample chamber along the z-direction exceeds the extension of the coil along the z-direction.
Such a flow-through microfluidic NMR-chip is known from .
Small-volume samples for nuclear magnetic resonance (NMR) spectroscopy consist for example of less than a few microliters of an analyte in solution. Such small samples are conveniently handled using microfluidic channels fabricated in different types of substrates, together with valves, pumps, and other miniaturized sample preparation and transportation means. NMR analysis in so-called lab-on-a-chip or micro total analysis systems (microTAS) is of great interest. However, because NMR has inherently a low sensitivity and since the NMR signal is proportional to the sample volume, signal-to-noise ratio becomes very weak for such small samples. One of the means to increase the sensitivity of the NMR experiment for small-volume sample is the use of miniaturized radio frequency (=RF) coils for signal detection. Coils which show dimensions of a few millimeters down to tens of micrometers can be fabricated by photolithography directly on the microfluidic substrate. Nevertheless, the quality of NMR spectra obtained so far from samples contained in microfluidic NMR-chips has been rather poor and appropriate coil-sample configurations remain to be designed in order to improve the NMR detection performance.
In  an NMR apparatus is disclosed wherein a planar, lithographic microcoil is fabricated onto a substrate onto which has been etched or grooved channels to serve as capillaries through which analytical compound flows.  describes an integrated miniaturized device for processing and NMR detection of liquid phase samples. Essential performance criteria of an NMR probe are its spectral resolution, sensitivity and homogeneity of the RF field of the microcoil (=B1 homogeneity). While the NMR detection performance is largely determined by the NMR coil—sample configuration, none of the above mentioned documents describes an arrangement yielding good NMR performance. In fact, the NMR performance of planar microcoils to date has been rather poor, in particular with respect to spectral resolution.
In  a rectangular Helmholtz coil geometry with the aim of improving B1 homogeneity is proposed, as shown in
In  a flow-through microfluidic NMR-chip is disclosed with an enlarged sample chamber and a planar circular coil. A proton spectrum of sucrose obtained from that prior art microfluidic NMR-chip configuration is illustrated in
Walton et al.  used a circular coil geometry 100 in combination with a spherical sample chamber 200 (
In order to improve spectral resolution, the configuration illustrated in
In summary, none of the prior art configurations simultaneously yielded a good spectral resolution, high sensitivity and large B1 homogeneity.
It is therefore an object of the invention to suggest a flow-through microfluidic NMR-chip with improved resolution, sensitivity as well as B1 homogeneity in order to achieve good NMR performance within microfluidic NMR-chips.
This object is achieved by the extension of the coil along the z-direction being larger than its extension along the y-direction. The coil comprises coil conductor sections which run mainly in the z-direction. The thickness of the substrate in x-direction is preferably between 100 μm and 2 mm, in particular between 200 μm and 2 mm, most preferably between 200 μm and 1 mm.
The basic idea of the invention is to adjust the geometry of the coil and the geometry of the sample chamber in order to avoid B0 field distortions on the one hand and to improve B1 homogeneity on the other hand.
Spectral resolution is a direct consequence of distortions of the static magnetic field B0 introduced by the NMR probe within the sample. In the case of a microfluidic NMR-chip, B0 distortion is mainly determined by the sample chamber shape as well as coil geometry and positioning of the wires with respect to the sample chamber. Sensitivity and B1 homogeneity are mainly determined by the characteristics of the B1 magnetic field produced by the NMR coil within the sample volume. The spatial dependence of the B1 field depends on the coil geometry and arrangement with the sample chamber.
Due to the elongated sample chamber distortions of the homogeneity of the static magnetic field in the central region of the sample chamber can be avoided or at least minimized. The inventive NMR-chip comprises a coil which is also elongated in z-direction. The center of the sample chamber and the center of the coil are preferably located at the same z-value. It is advantageous that the extension of the sample chamber in z-direction exceeds the extension of the coil in z-direction, in order to avoid negative effects at the edges of the sample chamber. Provided that the z-axis is aligned with the static magnetic field B0 this configuration, in which the sample chamber as well as a substantial portion of the coil are orientated in the z-direction, results in an improved B0 homogeneity, since the elongated sample chamber minimizes B0 distortion within the central part of the sample. The orientation of a substantial portion of the conducting wires along z-direction effects that no significant distortion of the B0 field within the sample volume takes place and therewith an improved spectral resolution can be achieved. Because of the orientation of the conducting wires along z-direction a homogeneous B1-field along the z-axis is produced. The inventive sample-coil arrangement improves the Signal to Noise ratio thus increasing sensitivity of the NMR-chip.
Compared to prior art, the inventive coil-sample configuration allows one to simultaneously improve spectral resolution while achieving high sensitivity and B1 homogeneity. The new configuration makes it possible to shim the sample using conventional shim systems since small scale distortions through the coil and chip are neglectable with this invention and only large scale distortions of the probe remain.
In a preferred embodiment the coil has a rectangular shape. In this case a maximum quantity of the conductor sections is oriented in z-direction therewith not disturbing the magnetic field B0 within the sample chamber. Note that this argument scales and thus is true for all sizes of coil ranging from 50 μm to several millimeter. However a convential shim system is fixed and does not scale with the coil. While there is not much influence on a small coil (e.g. 50 μm) it may have some influence for larger coils (e.g. some millimeters). Because of this, it should be noted that other coil geometries which show an elongated shape can also be suitable for lager coils, e.g. an elliptic shaped coil. In this case most of the conductor sections do not run parallel to the z-direction. Yet each conductor section can theoretically be split in a parallel part (projection on the z-direction) and a perpendicular part (projection perpendicular to z-direction). The object of the invention is achieved if the parallel parts of most of the conductor sections exceed the perpendicular part.
The ratio of the extension of the coil along the z-direction and the extension of the coil along the y-direction is preferably between 1.1 and 5.
It is advantageous if one coil is arranged on both outer surfaces of the substrate, which are connected to form a Helmholtz arrangement. With this configuration the B1 homogeneity can be further improved. The Helmholtz arrangement consists preferably of two mirror symmetric planar coils.
A preferred embodiment of the inventive NMR-chip provides a plurality of coils, in particular two coils, wherein each coil is tuned to a plurality of different frequencies. Therewith signals from different nuclei can be received.
In an advantageous development of this embodiment the coils are inductively decoupled. This leads to improved performance of multinuclear NMR experiments. It should be noted that any reduction of the difference in susceptibility is of advantage, it need not being “perfectly” matched.
Further preferred is an embodiment in which the conductor sections of the coils are arranged multilayered. Also microcoil cross-wires are preferably arranged multilayered. As a result, inductively decoupled coils can be fabricated onto one surface of the substrate in the same production process.
In a particularly preferred embodiment one of the coils is rectangular and the other coil forms a butterfly arrangement. The odd-symmetry of the x-component of the rf field produced by the butterfly coil in the xy plane allows one to efficiently decouple both coils.
In order to minimize distortion of the static magnetic field it is preferred that the magnetic susceptibilities of the coil conductor sections are matched to the susceptibilities of their respective environment, for example to nitrogen gas surrounding the coil wires. Microcoil cross-wires are then also matched to the susceptibilities of their respective environment.
It is advantageous when the coil is equipped with integrated shielding plates. The shielding plates prevent the RF field B1 to penetrate the sample in regions external from the coil thereby improving the field distribution. The shielding plates may comprise a copper layer acting as eddy current shielding.
The material of the coil comprises preferably copper, gold and/or silver.
It is advantageous if the ratio of the extension of the sample chamber along the z-direction and the extension of the coil along the z-direction is greater than 1.5. The sample chamber exceeds the extension of the coil in z-direction thereby reducing B0-distortion, which reduces with increasing length (extension in z-direction) of the sample chamber.
In a preferred embodiment of the inventive NMR-chip the substrate comprises two parts, which are bonded together. In at least one of the substrate parts an elongated channel is etched which form the sample chamber when the substrate parts are bonded together.
The substrate is preferably dielectric and electrical insulating, in particular made of glass, quartz or silica. In particular borosilicate glass is suitable as substrate material.
In a preferred embodiment the magnetic susceptibility of the substrate is matched to the susceptibility of a solvent, in particular to the susceptibility of water. Thus no susceptibility changes occur at the interface of the substrate and the solvent of the sample. Yet, this is only possible for one selected sample (preferable one which is investigated most often) or for an imaginary “averaged” sample, whose susceptibility is the average susceptibility of the most common samples.
It is preferred that the centers of the sample chamber, of the coil and of the substrate coincide within the yz-plane. This minimizes B0 distortion and facilitates shimming.
In a preferred embodiment the NMR-chip shows a length along the z-direction of less than 50 mm, in particular less than 25 mm, most preferably less than 20 mm, and a width along the y-direction of less than 30 mm, in particular less than 15 mm.
In a special embodiment two or more sample inlets are provided upstream of the sample chamber. Different samples can be mixed directly within the inventive NMR-chip.
The invention also concerns a NMR apparatus comprising a superconducting magnet, a NMR-spectrometer and a probe with a NMR-chip as described above, wherein the NMR-chip is aligned along a static magnetic field in z-direction, which is produced from the superconducting magnet in operation.
Further advantages can be extracted from the description and the enclosed drawing. The features mentioned above and below can be used in accordance with the invention either individually or collectively in any combination. The embodiments mentioned are not to be understood as exhaustive enumeration but rather have exemplary character for the description of the invention.
The invention is shown in the drawing.
A cut-out of the inventive NMR-chip is disclosed in
The substrate 5 has a length L1, a width W1, is preferable made from a glass material or quartz. It comprises two substrate parts 51, 52 with thicknesses t1, t2 which are bonded together. An elongated channel is etched on the lower surface of a first planar substrate part 51 and on the upper surface of the second substrate part 52. The sample chamber 2 can also be formed by etching only one of the substrate parts 51, 52, as shown in
The NMR sample chamber 2 is formed by the cavities etched in the first 51 and second planar glass substrate part 52, by assembling the substrate parts 51, 52 onto each other. The sample chamber 2 has a finite length L2, a width W2, and a channel depth d1, preferable with the following dimensions:
The coil 1 has closing cross-wire sections 12 perpendicular to the z-axis. The length L3 of the coil 1 is greater than its width W3, thereby causing an elongated shape of the coil 1. Preferably coil 1 has a rectangular shape, but can also have another elongated shape, such as an ellipsoid. In case coil 1 is used as a proton coil (i.e. for exciting 1H-nuclei) its wires are advantageously made of copper (Cu), silver (Ag) or gold (Au). For optional compensation of magnetic susceptibility other materials may be added. Both single and multiple turn coils are suitable for NMR-spectroscopy purposes. The preferred dimensions for a rectangular coil 1 are the following:
An arrangement allowing one to eliminate those negative B1 field values produced by the coil cross-wires 12 is disclosed in
In addition to B0 distortion 31 produced by the finite length L2 of the sample chamber, a B0 distortion 32 produced by diamagnetic coil cross-wires 12 is illustrated in
An embodiment of the invention featuring two coils 1, each on one external surfaces of the substrate 5 is disclosed in
An embodiment of the present invention comprising two sample inlets 21 a, 21 b upstream of the sample chamber 2 is shown in
Compared to prior art, the present invention improves NMR detection performance within microfluidic NMR-chips in many respects. These improvements are illustrated for two examples of possible embodiments.
The first example deals with a flow-through microfluidic NMR-chip with an integrated Helmholtz microcoil as shown in
This example embodiment also provided excellent B1 homogeneity performance as illustrated in
The second example deals with another embodiment of the present invention comprising two magnetically decoupled coils tuned to two different frequencies, as shown in
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|Cooperative Classification||G01R33/302, G01R33/307|
|European Classification||G01R33/30S, G01R33/30M|
|Oct 3, 2007||AS||Assignment|
Owner name: BRUKER BIOSPIN AG, SWITZERLAND
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MASSIN, CHARLES;FEY, MICHAEL;REEL/FRAME:019970/0159;SIGNING DATES FROM 20070910 TO 20070914
|Mar 12, 2013||FPAY||Fee payment|
Year of fee payment: 4
|Apr 26, 2017||FPAY||Fee payment|
Year of fee payment: 8